Discovery of Low-Molecular Weight Antagonists of Substance P: Recent Developments and Prospects as a Therapeutic Agent.

The creation of antagonists of substance P (SP) has been the focus of intensive research because of their potential as therapeutic agents. A conventional for an SP antagonist is the synthesis of SP analogs in which amino acids are substituted or some peptide bonds are modified. Another useful method is the screening of compounds from a sample file. This method, called random screening, led to the discovery of novel and potent non-peptide antagonists. Apart from these two strategies, we were able to design low-molecular weight antagonists from a known peptide lead. The search for the essential part for receptor binding, improvement of the stability against enzymatic metabolism, and chemical modifications led to a potent tripeptide (4, FR 113680). The molecular size of this tripeptide was reduced to a dipeptide structure such as 13, through newly designed branched tripeptides (510). Further optimization of the lysine part of 13 into (2 S, 4 R) Hyp and subsequent modification of the side chain parts culminated in the potent dipeptide antagonist (15, FK 888). The pharmacological profile of 15 as an antiasthma agent is also presented.